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Biomedical subjects

G M Crippen

Publications and source records attributed to G M Crippen.

At least 19 recordsLinked to original sources
PubMed1992

Contact potential that recognizes the correct folding of globular proteins.

We have devised a continuous function of interresidue contacts in globular proteins such that the X-ray crystal structure has a lower function value than that of thousands of protein-like alternative conformations. Although we fit the adjustable parameters of the potential using only 10,000 alternative structures for a selected training set of 37 proteins, a grand total of 530,000 constraints was satisfied, derived from 73 proteins and their numerous alternative conformations. In every case where the native conformation is adequately globular and compact, according to objective criteria we have developed, the potential function always favors the native over all alternatives by a substantial margin. This is true even for an additional three proteins never used in any way in the fitting procedure. Conformations differing only slightly from the native, such as those coming from crystal structures of the same protein complexed with different ligands or from crystal structures of point mutants, have function values very similar to the native's and always less than those of alternatives derived from substantially different crystal structures. This holds for all 95 structures that are homologous to one or another of various proteins we used. Realizing that this potential should be useful for modeling the conformation of new protein sequences from the body of protein crystal structures, we suggest a test for deciding whether a nearly correct approximation to the native conformation has been found.

Animals↗
PubMed1991

Prediction of protein folding from amino acid sequence over discrete conformation spaces.

Predicting the three-dimensional structure of a protein given only its amino acid sequence is a long-standing goal in computational chemistry. In the thermodynamic approach, one needs a potential function of conformation that resembles the free energy of the real protein to the extent that the global minimum of the potential is attained by the native conformation and no other. In practice, this has never been achieved with certainty because even with greatly simplified representations of the polypeptide chain, there are an astronomical number of local minima to examine. If one chooses instead a protein representation with only a large but manageable number of discrete conformations, then the global preference of the potential for the native can be directly verified. Representing a protein as a walk on a two-dimensional square lattice makes it easy to see that simple functions of the interresidue contacts are sufficient to globally favor a given "native" conformation, as long as it is a compact, globular structure. Explicit representation of the solvent is not required. Another more realistic way to confine the conformational search to a finite set is to draw alternative conformations from fragments of larger proteins having known crystal structure. Then it is possible to construct a simple function of interresidue contacts in three dimensions such that only 8 proteins are required to determine the adjustable parameters, and the native conformations of 37 other proteins are correctly preferred over all alternative conformations. The deduced function favors short-range backbone-backbone contacts regardless of residue type and long-range hydrophobic associations. Interactions over long distances, such as electrostatics, are not required.

Amino Acid Sequence↗
PubMed1991

Fast drug-receptor mapping by site-directed distances: a novel method of predicting new pharmacological leads.

The searching and characterization of large chemical databases has recently provoked much interest, particularly with respect to the question of whether any of the compounds in the database could serve as new leads to a compound of pharmacological interest. This paper introduces a fast and novel method of determining whether any of a given series of compounds are able, on geometrical grounds, to interact with an active site of interest. The C program written to implement the method is able to make a qualitative prediction for a given compound in about 1 s per structure (for drug-sized molecules), while still permitting the compound complete conformational freedom. However, the algorithm is sufficiently flexible to permit distance constraints to be placed on the molecules while docking. The test system studied was a family of Baker's triazines docking into the active site of dihydrofolate reductase (DHFR), as defined by a methotrexate/NADPH complex.

Algorithms↗
PubMed1991

Dimensional oscillation. A fast variation of energy embedding gives good results with the AMBER potential energy function.

The structure of the AMBER potential energy surface of the cyclic tetrapeptide cyclotetrasarcosyl is analyzed as a function of the dimensionality of coordinate space. It is found that the number of local energy minima decreases as the dimensionality of the space increases until some limit at which point equipotential subspaces appear. The applicability of energy embedding methods to finding global energy minima in this type of energy-conformation space is explored. Dimensional oscillation, a computationally fast variant of energy embedding is introduced and found to sample conformation space widely and to do a good job of finding global and near-global energy minima.

Computer Simulation↗
PubMed1990

Global energy minimization by rotational energy embedding.

Given a sufficiently good empirical potential function for the internal energy of molecules, prediction of the preferred conformations is nearly impossible for large molecules because of the enormous number of local energy minima. Energy embedding has been a promising method for locating extremely good local minima, if not always the global minimum. The algorithm starts by locating a very good local minimum when the molecule is in a high-dimensional Euclidean space, and then it gradually projects down to three dimensions while allowing the molecule to relax its energy throughout the process. Now we present a variation on the method, called rotational energy embedding, where the descent into three dimensions is carried out by a sequence of internal rotations that are the multidimensional generalization of varying torsion angles in three dimensions. The new method avoids certain kinds of difficulties experienced by ordinary energy embedding and enables us to locate conformations very near the native for avian pancreatic polypeptide and apamin, given only their amino acid sequences and a suitable potential function.

Apamin↗
PubMed1990

Voronoi binding site model of a polycyclic aromatic hydrocarbon binding protein.

A three-dimensional Voronoi binding site model has been formulated from a series of competitors for the binding site on a recently isolated polycyclic aromatic hydrocarbon binding protein (PBP) from mouse liver. The PBP binds polycyclic aromatic hydrocarbons, such as benzo[a]pyrene (B[a]P), with high affinity and shows other characteristics associated with receptor-ligand complexes. Altogether, the in vitro binding constant of seven molecules were used to deduce the geometry and the energetics of a possible site model consisting of five regions: one tetrahedron-shaped finite central hydrophobic pocket, one infinite region representing access to the solvent, and three strongly repulsive regions representing the sterically forbidden walls of the pocket. The model then predicted the binding energies correctly for nine additional competitors and suggests that competition of monoaromatic (benzene) derivatives with B[a]P would be weak.

Animals↗
PubMed1990

Modeling the benzodiazepine receptor binding site by the general three-dimensional structure-directed quantitative structure-activity relationship method REMOTEDISC.

A novel computer-aided receptor modeling method, REMOTEDISC [J. Med. Chem. 32:746-756 (1989)], has been used to analyze the inhibition of labeled diazepam binding by 29 benzodiazepine receptor ligands. The method uses the three-dimensional structure, conformational energy, and important atom-based physicochemical properties to model the hypothetical binding site cavity. The model not only consists of the geometry of the binding cavity but also gives the weight of the various physicochemical properties of the ligands at different parts of the binding cavity responsible for their binding to the receptor. The model fitted the binding data with a correlation coefficient of 0.980, a SD of 0.223, and an explained variance of 0.898. It suggested that a small hydrophilic group is favored at position 1 of the benzodiazepine ring, the C = O region of this ring is favored by dispersive atoms and positive charge, the 4'-substituent of the 5-phenyl group is subject to strong steric repulsion, the 7- position is favored to be a hydrophilic group, and the 8- and 9- positions and their substituents are favored to be dispersive as well as hydrophilic groups. It also suggested that the substitution of the 5-phenyl group by the more dispersive 2-thiophene may increase the binding affinity. The model was allowed to predict the binding affinity data of five compounds with extensive variation of the structure from the training set; the prediction for four compounds was excellent. Some of the problems of the method have been discussed with their possible remedies.

Benzodiazepines↗
PubMed1989

Analysis of the in vitro antiviral activity of certain ribonucleosides against parainfluenza virus using a novel computer aided receptor modeling procedure.

The in vitro antiviral activity of 28 nucleosides against the parainfluenza virus type 3 has been analyzed by using a novel computer aided receptor modeling procedure. The method involves an extensive modification of our earlier work (Ghose, A. K.; Crippen, G. M. J. Med. Chem. 1985, 28, 333). It presents a more straightforward algorithm for the steps that suffered from subjectivity in the earlier method. The method first determines the possible low-energy conformations of the nucleosides, and assigns a priority value for each conformation of each molecule. It then performs the following steps repeatedly, until it finds an acceptable solution. Starting from the conformation of highest priority, the various energetically allowed conformations of the other molecules are superimposed on it. On the basis of the physicochemical property matching (or overlapping), the best superposition is determined. The superimposed molecules are dissected into a minimum number of parts and the local physicochemical properties at different regions are correlated with their binding data (antiviral activity). A modified version of distance geometry has been used for geometric comparison of the structure of the molecules. On the basis of the virus rating (VR) of 28 ribonucleosides, this procedure hypothesized the minimum-energy conformation of 6-(methylthio)-9-beta-D-ribofuranosylpurine as a reference conformation and used three physicochemical properties, namely hydrophobicity, molar refractivity, and formal charge density for property matching. The binding-site cavity was divided into seven regions or pockets to differentiate the nature of interaction quantitatively. The model suggests that the 2- and 3-positions of the purine ring and the corresponding atoms of the other rings get some steric repulsion, and nucleosides having a single five-membered heterocyclic ring will better fit this virus. The methylthio group gets a strong attraction from dispersive interaction. Both hydrophilic and dispersive groups are attractive here. Although our calculation supports the previously suggested active conformation of ribavirin, it shows that it is not the global minimum-energy conformation. The difference lies in the orientation of the amide group. The calculated viral rating from this model showed a correlation coefficient of 0.971 with the observed values, and the explained variance and the standard deviation of the fit were 0.880 and 0.125, respectively.

Antiviral Agents↗
PubMed1988

Use of augmented Lagrangians in the calculation of molecular conformations by distance geometry.

Distance geometry is a technique widely used to find atomic coordinates that agree with given upper and lower bounds on the interatomic distances. It is successful because it chooses at random some relatively good "trial coordinates" that take into account the whole molecule and all constraints at once. Customarily, these trial coordinates must be refined by minimizing a penalty function until the structure agrees with the original bounds. Here we present an alternative to minimizing the penalty function, which has the advantage of more precisely satisfying the bounds, showing more clearly when the bounds are mutually contradictory, and simultaneously optimizing an objective function subject to precise satisfaction of the bounds.

Enkephalin, D-Penicillamine (2,5)-↗
PubMed1987

Atomic physicochemical parameters for three-dimensional-structure-directed quantitative structure-activity relationships. 2. Modeling dispersive and hydrophobic interactions.

In an earlier paper (Ghose A. K.; Crippen, G. M. J. Comput. Chem. 1986, 7, 565) the need of atomic physicochemical properties for three-dimensional-structure-directed quantitative structure-activity relationships was demonstrated, and it was shown how atomic parameters can be developed to successfully evaluate the molecular water-1-octanol partition coefficient, which is a measure of hydrophobicity. In the present work the atomic values of molar refractivity are reported. Carbon, hydrogen, oxygen, nitrogen, sulfur, and halogens are divided into 110 atom types of which 93 atomic values are evaluated from 504 molecules by using a constrained least-squares technique. These values gave a standard deviation of 1.269 and a correlation coefficient of 0.994. The parameters were used to predict the molar refractivities of 78 compounds. The predicted values have a standard deviation of 1.614 and a correlation coefficient of 0.994. The degree of closeness of the linear relationship between the atomic water-1-octanol partition coefficients and molar refractivities has been checked by the correlation coefficient of 89 atom types used for both the properties. The correlation coefficient has been found to be 0.322. The low value suggests that both parameters can be used to model the intermolecular interaction. The origin of these physicochemical properties and the types of interaction that can be modeled by these properties have been critically analyzed.

Models, Theoretical↗
PubMed1985

Use of physicochemical parameters in distance geometry and related three-dimensional quantitative structure-activity relationships: a demonstration using Escherichia coli dihydrofolate reductase inhibitors.

In earlier distance geometry related three-dimensional quantitative structure-activity relationships (Ghose, A. K.; Crippen, G. M. J. Med. Chem. 1984, 27, 901) the interactions of the ligand atom or group with the receptor site were evaluated empirically by using mathematical optimization techniques, without considering their physicochemical properties. In the present work we show how to use various physicochemical parameters in our three-dimensional receptor mapping. We have developed a model for E. coli DHFR using the inhibition data of 25 pyrimidines and 14 triazines. It gave a correlation coefficient of 0.893 and standard deviation of 0.530. It successfully predicted the binding data of five pyrimidines and five triazines.

Binding Sites↗
PubMed1985

Sidechain and backbone potential function for conformational analysis of proteins.

An improved potential function has been devised for the calculation of protein conformations. Each amino acid residue is represented by two points. The mainchain is traced by the sequence of C alpha atoms, and the details of sidechain structure and interactions are represented by a representative sidechain atom. This potential function has been developed from a data base of 22 high resolution protein crystal structures and includes the components of an earlier potential developed from a similar data base where each amino acid residue is represented by only its C alpha atom. In virtually all aspects of testing, the present potential betters the previous single-point potential, and is shown to be useful in the simulation of protein folding.

Amino Acid Sequence↗
PubMed1979

Distance geometry approach to rationalizing binding data.

A new method is presented for calculating a type of quantitative structure-activity relationship, given experimental data on the binding affinity of a series of ligands to a receptor site on a protein. All ligands are presumed to have known chemical structure but may be conformationally flexible, and all are presumed to bind to the same, single, fairly rigid site of the (pure) receptor protein molecule. Given the experimentally determined free energies of binding of the ligand molecules, possible binding sites are deduced in terms of geometry and the chemical character of the various parts of the site. A test of the method is given for a series of chymotrypsin inhibitors and for a series of dihydrofolate reductase inhibitors. The proposed dihydrofolate reductase site suggests that a quinazoline inhibitor may rock between two different binding nodes depending on the pK of the ring N(1).

Binding Sites↗
PubMed1979

Protein densities.

The calculation of protein densities from atomic coordinates is not straight-forward and requires very careful attention to the determination of the protein-solvent boundary. Interior densities are more readily obtained and are in reasonable agreement with those estimated from solvent accessibility studies. The interior of globular proteins has very significant density inhomogenities on a scale of 100--1000 A3. The interior densities range from less than 0.5 g/cm3 to over 3 g/cm3. The low local densities are primarily associated with clusters of nonpolar sidechains while the high local density regions arise from the protein backbone secondary structures: helices and beta sheets. We show a rough correlation between local density and local polarity.

Densitometry↗
PubMed1979

Distance constraints on macromolecular conformation.

Many physico-chemical studies are made on proteins to determine something of their solution conformation. For example the coat protein of Tobacco Mosaic Virus has been subjected to more non-crystallographic experimental studies to determine its native conformation than perhaps any other protein. Yet the sum of the experimentally determined constraints on its tertiary structure are surprisingly inadequate to fix its conformation. We are able to detect and remove minor inconsistencies in the data and then calculate a sampling of conformations consistent with all the data, which differ among themselves by r.m.s. deviations of the respective interresidue distances ranging from 5.7 angstrom to 15.8 angstrom. Some individual interresidue distances differ by as much as 50 angstrom from structure to structure. In order to restrict the range of possible conformations to something corresponding to the errors in a 10 angstrom resolution X-ray crystal structure, chemical and spectroscopic studies will have to be much more detailed than anything done to date. Our calculations appear to be useful in deciding which further experiments would be most productive.

Chemical Phenomena↗